Dose intensity is critical in diffuse large B-cell lymphoma (DLBCL) but can be limited by toxicity risk. The influence of treatment intensity, illness burden, and socioeconomic status (SES) on survival in DLBCL has not been evaluated on a patient-level analysis. We performed a retrospective study of 344 patients with DLBCL from an urban academic cancer center; 55% received lower intensity treatment (average relative dose intensity [ARDI] of cyclophosphamide and doxorubicin <0.9). ARDI, performance status (PS), Charlson comorbidity index (CCI), and double expressor lymphoma (DEL) were associated with progression-free (PFS) and overall survival (OS). Lower ARDI was linked to worse illness burden, treatment intolerance, and higher-risk disease features. Lower ARDI was associated with worse PFS (HR 2.59, p < 0.001) and OS (HR 4.26, p < 0.001) as well as DLBCL progression (sHR 1.86 p = 0.004) and non-relapse mortality (NRM) (sHR 5.45 p = 0.001) in competing risks analysis. Comprehensive multidisciplinary care is needed to reduce the risks associated with undertreatment in DLBCL.

Castleman disease is a rare, heterogeneous group of lymphoproliferative disorders whose imaging characteristics can resemble malignancy. We present a case of a patient who initially presented with intermittent hypertension, palpitations, and chest pain. Despite a negative biochemical workup, CT imaging revealed a left retroperitoneal mass intimately associated with the left adrenal gland with 68Ga-DOTATATE positron emission tomography-computed tomography (PET/CT) detecting uptake in the mass as well as several left para-aortic lymph nodes and bone lesions. Based on the imaging findings, the patient was taken to the operating room for resection of what was presumed to be a metastatic neuroendocrine tumour. However, the diagnosis on histopathological examination was hyaline-vascular Castleman disease. While DOTATATE PET/CT has high sensitivity and specificity for neuroendocrine tumours (NETs), this case report highlights that non-neuroendocrine pathology may result in DOTATATE uptake, and that Castleman disease should be considered when encountering DOTATATE-positive masses on imaging.

Peripheral T-cell lymphomas (PTCL) are aggressive hematologic cancers characterized by complex tumor microenvironments (TME) with rich hematopoietic and non-hematopoietic elements. A deeper understanding of both the malignant T cells and the TME could reveal therapeutic vulnerabilities in these lymphomas, which respond poorly to conventional chemotherapy. However, the cellular architecture, transcriptional programs and tumor cell-TME interactions have not been comprehensively characterized in PTCL. Here, we performed an integrated, multiomic analysis, including single-nucleus RNA sequencing (snRNA-seq), bulk RNA sequencing, and targeted mutational profiling, on archival samples from 29 frozen PTCL biopsies- including T follicular helper cell lymphoma (TFHL) and PTCL, not otherwise specified (PTCL, NOS), along with six control lymph nodes and tonsils. After rigorous quality control, a total of 230,174 cells were analyzed. Unsupervised clustering following dimensionality reduction revealed 13 distinct benign and malignant T-cell states and 42 transcriptionally unique cell types (14 B-cell subsets, 14 myeloid subsets, 6 endothelial cell subsets, and 8 non-endothelial stromal cell subsets), many of which have not been previously characterized in PTCL. Analysis of malignant T cells revealed substantial heterogeneity in PTCL, NOS, linked to chromosomal abnormalities, while TFHL tumors exhibited less genetic and transcriptional variability and were associated with specific transcriptional programs driven by RHOA G17V and IDH2 mutations. Both subtypes showed enrichment in MYC targets, TNF-α signaling, mTOR signaling, mitosis, and cell cycle pathways, whereas MAPK and STAT5 signaling were uniquely enriched in TFHL. TME analysis revealed shared hallmarks across PTCL, NOS and TFHL, including B-cell depletion and expansion of exhausted CD8+ T cells and tumor-associated macrophages (Mφ). In contrast, enrichment of immunoblasts, regulatory T cells, and non-endothelial stromal cells represents a disease-specific alteration in TFHL. Decomposition of transcriptomic profiles from all cell types present in PTCL and control samples using non-negative matrix factorization (NMF) identified 104 gene expression programs, 36 of which showed differential per-sample activity between PTCL TME and normal controls. Correlation analysis of PTCL-specific gene programs revealed five multicellular modules, including two non-overlapping modules: one characterized by follicular dendritic cells (FDCs) and inflammatory Mφ, and the other by cancer-associated fibroblasts (CAFs) and M2-like Mφ. Cell-cell communication analysis further identified TNF-α and TGF-β as key ligands orchestrating these TME modules. Finally, computational modeling and in vivo perturbation of these interactions uncovered therapeutic vulnerabilities, including a previously unrecognized role for the TGF-β pathway in supporting PTCL tumor growth. Together, these findings provide new insights into PTCL biology and establish a foundation for TME-informed therapeutic strategies, offering potential avenues for patient stratification and targeted intervention.

Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might bene fi t patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten -independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open -capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T -cell lymphoma; more ef fi cient therapy is needed.

Abstract Peripheral T-cell lymphomas (PTCL) are heterogeneous and highly aggressive hematologic malignancies with dismal outcomes, highlighting the need for novel targeted therapies. PTCLs are characterized by complex tumor-microenvironment (TME) ecosystems with low tumor cell content, admixed with rich immune infiltrates and stromal elements correlated with clinical outcomes. Direct targeting of the TME is an attractive strategy for PTCLs; however, the specific mechanisms that regulate the interdependence between lymphoma and TME remain poorly understood, hampering the development of TME-directed therapies. Our previous work based on driver genetic alterations in PTCL patients and genetic mouse models identified an important role of these driver mutations in remodeling the TME (Cortes et al., 2022). To address the specific role and mechanisms of tumor cell-TME interactions in the pathogenesis of PTCL, we developed a novel experimental platform and cutting-edge computational methodologies using single-nucleus RNAseq analysis to comprehensively profile lymphoma cells and their microenvironment from 27 PTCL patient samples of two major nodal pathologic subtypes, including 18 Nodal T follicular helper cell lymphomas (TFHcL) and 9 PTCL, not otherwise specified (PTCL, NOS). Our approach allowed the identification and in-depth characterization of tumor cells, lymphoid and myeloid TME, and vascular endothelium and non-endothelial stromal cells, which were challenging to capture with conventional single-cell RNAseq. The malignant T-cells in PTCL, NOS were grouped into patient-specific clusters demonstrating significant inter-tumor heterogeneity associated with diverse and frequently complex chromosomal abnormalities identified by copy number variation (CNV) analysis. In contrast, malignant TFHcL cells show a low degree to no apparent chromosomal abnormalities and divide into two major transcriptional subclusters, with tumor cells from the same patient falling into one of the two subclusters. Additionally, genomic profiles of TFHcL tumors revealed that the inter-tumor transcriptional heterogeneity of TFHcL tumor cells was strongly associated with the driver RHOA G17V mutation status. To profile oncogenic pathways critical for PTCL growth, we compared PTCL tumor cells to normal CD4 T-cells from reactive lymphoid tissue. PTCL, NOS and TFHcL tumor cells were equally enriched in the TCR signaling pathway, mitosis, and cell cycle related genes. However, exploitation of KRAS and cytokine-driven inflammatory signals was prevalent in TFHcL but not PTCL, NOS tumor cells. Analysis of the immune TME identified an increase in T regulatory cells, CD8 T-cells, immunoblasts, and macrophages in TFHcL. Furthermore, while dysregulated B-cells with heightened cytokine-driven inflammatory signals were unique to TFHcL, inflammatory macrophages and classic dendritic cells (cDC) were prominent in the TME of both subtypes. Our results uncover shared and subtype-specific pathogenic features in PTCL and pave the way for designing novel precision therapies for PTCL patients. Citation Format: Wen-Hsuan Wendy Lin, Anqi W Wang, Bobby B Shih, Jean-Baptiste F Reynier, Laura Quevedo Palacio, Craig Soderquist, Ryan D Najac, Cindy Ma, Govind Bhagat, Adolfo A Ferrando, Raul Rabadan, Teresa Palomero. Single-cell transcriptomics reveals shared and subtype-specific vulnerabilities of the tumor-microenvironment ecosystems in peripheral T-cell lymphomas [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PR05.

Next-generation sequencing is becoming increasingly important for the diagnosis, risk stratification, and management of patients with established or suspected myeloid malignancies. These tests are being incorporated into clinical practice guidelines and many genetic alterations now constitute disease classification criteria. However, the reimbursement for these tests is uncertain. This study analyzed the clinical impact, ordering practices, prior authorization, and reimbursement outcomes of 505 samples from 477 patients sequenced with a 50-gene myeloid next-generation sequencing panel or a 15-gene myeloproliferative neoplasm subpanel. Overall, 98% (496 of 505) of tests provided clinically useful data. Eighty-nine percent of test results, including negative findings, informed or clarified potential diagnoses, 94% of results informed potential prognoses, and 19% of tests identified a potential therapeutic target. Sequencing results helped risk-stratify patients whose bone marrow biopsy specimens were inconclusive for dysplasia, monitor genetic evolution associated with disease progression, and delineate patients with mutation-defined diagnoses. Despite the clinical value, prior authorization from commercial payors or managed government payors was approved for less than half (45%) of requests. Only 51% of all cases were reimbursed, with lack of medical necessity frequently cited as a reason for denial. This study demonstrates the existence of a substantial gap between clinical utility and payor policies on test reimbursement.

The authors present two cases of conjunctival pediatric- type follicular lymphoma. A 14-year-old Black boy and 14-year-old Black girl were each referred for evaluation of a painless salmon-colored conjunctival lesion. Both patients underwent excisional biopsy. Histopathology demonstrated follicles with germinal centers composed of atypical B-cells with high Ki67 proliferation index, positive staining for CD20, CD10, and BCL6, and negative for BCL2. This series contributes two cases to the limited literature and presents the first case reported in a female. [ J Pediatr Ophthalmol Strabismus. . 2024;61(4):e33-e38.]

A 74-year-old man with chronic kidney disease and splenic marginal zone lymphoma, diagnosed 3 years ago, status post bendamustine and rituximab and now on zanubrutinib due to recurrence, presented with acute kidney injury and proteinuria. On admission, he had a serum creatinine level of 2.7 mg/dl (baseline, ≈1.9 mg/dl), a urine protein-to-creatinine ratio of 5 g/g, and a serum albumin level of 3.2 g/dl. Serum protein electrophoresis showed IgGκ M protein. Serum free light chain ratio was 3.2.

PDF - 106K, Contains the legends for Supplementary Figures 1-6 and Supplementary Tables 1-7.

XLSX - 1231K, Supplementary Table 1: List of genes deleted in 75 to 100% of the end-stage *PTEN tumors Supplementary Table 2: List of genes showing copy number gains in *PTEN end-stage and *PTEN/p53 mouse tumors. Supplementary Table 3: Genes that were deleted in 75-100% of *PTEN end-stage mouse tumors and at least 10% of human tumors within one of the four GBM subtypes mapped to their chromosomal location in the human genome. Supplementary Table 4: List of gene deletions that were specific for one of the four GBM subtypes. Supplementary Table 5: Correlation of proneural-specific genetic alterations and deletions identified by cross-species comparison. Supplementary Table 6: Spearman correlation for Verhaak gene sets show highest correlation for human proneural GBM subtype for 21 dpi *PTEN tumors, end-stage *PTEN tumors and *p53 end-stage tumors. Supplementary Table 7: MR identified from NB versus *PTEN 21 dpi and NB versus *PTEN end-stage mouse MARINas, and human NB versus proneural GBM (TCGA) MARINa.

PDF - 1816K, Supplementary Figure 1: CGH probe for Cre-mediated Pten deletion provides a surrogate of tumor DNA content for mouse tumors. Supplementary Figure 2: The genomic architecture of mouse tumor gene deletions suggests independent selection pressure for genes within the same deletion in human tumors. Supplementary Figure 3: Mouse and Human Proneural GBM share a common regulatory network. Supplementary Figure 4: *PTEN/p53 tumors rapidly progress and acquire the histological features of GBM. Supplementary Figure 5: *Pten tumors acquire and express mutations in p53. Supplementary Figure 6: *p53 tumors develop the histological features of GBM, and have an intermediate survival between *PTEN and *PTEN/p53 tumors.

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Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12–31 months and ongoing).

Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those infected with human immunodeficiency virus (HIV) and solid organ allograft recipients. Most prior studies have focused on delineating the clinico-pathological features and genetic attributes of HIVrelated PBL, in which MYC deregulation, Epstein-Barr virus (EBV) infection and, more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBL is not well characterized and data on underlying genetic alterations are limited. This led us to perform comprehensive histopathological and immunophenotypic evaluation and targeted sequencing of 18 samples from 11 patients (8 males, 3 females; age range, 12-76 years) with PT-PBL; eight de novo and three preceded by other types of post-transplant lymphoproliferative disorders. Post-transplant PBL displayed morphological and immunophenotypic heterogeneity and some features overlapped those of plasmablastic myeloma. Six (55%) cases were EBV positive and five (45%) showed MYC rearrangement by fluorescence in situ hybridization. Recurrent mutations in epigenetic regulators (KMT2/MLL family, TET2) and DNA damage repair and response (TP53, mismatch repair genes, FANCA, ATRX), MAP kinase (KRAS, NRAS, HRAS, BRAF), JAK/STAT (STAT3, STAT6, SOCS1), NOTCH (NOTCH1, NOTCH3, SPEN), and immune surveillance (FAS, CD58) pathway genes were observed, with the mutational profiles of EBV+ and EBV– cases exhibiting both similarities and differences. Clinical outcomes also varied, with survival ranging from 0-15.9 years after diagnosis. Besides uncovering the biological heterogeneity of PT-PBL, our study highlights similarities and distinctions between PT-PBL and PBL occurring in other settings and reveals potentially targetable oncogenic pathways in subsets of the disease.

Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract are uncommon clonal neoplasms that have a protracted clinical course and limited response to therapy. In recent years, advances in the immunophenotypic, genetic, and clinical characterization of these disorders have led to increased awareness and a better understanding of disease pathogenesis. However, many questions remain unanswered, including those concerning the cell(s) of origin, inciting immune or environmental factors, and the molecular pathways underlying disease progression and transformation. In this review, we discuss recent findings regarding the immunophenotypic and genomic spectrum of these lymphoproliferative disorders and highlight unresolved issues.

This chapter describes the clinical, pathological, and genetic characteristics of enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma, and refractory celiac disease (RCD), a rare lymphoproliferative disorder that is a precursor to a subset of EATLs. It discusses current and emerging treatment options. Epidemiologic studies indicate a low prevalence of RCD in the community. In contrast to EATL, a female predominance is observed in RCD. Chemotherapy and stem-cell transplantation have been used for refractory RCD II, but these therapies have shown limited benefit with regard to long term disease control and are associated with substantial adverse effects. Future studies need to identify genetic and other risk factors for the progression of RCD to EATL.

Refractory celiac disease type II (RCD II), also referred to as “cryptic” enteropathy-associated T-cell lymphoma (EATL) or “intraepithelial T-cell lymphoma,” is a rare clonal lymphoproliferative disorder that arises from innate intraepithelial lymphocytes. RCD II has a poor prognosis and frequently evolves to EATL. The pathogenesis of RCD II is not well understood and data regarding the immunophenotypic spectrum of this disease and underlying genetic alterations are limited. To gain further biological insights, we performed comprehensive immunophenotypic, targeted next-generation sequencing, and chromosome microarray analyses of 11 RCD II cases: CD4−/CD8− (n=6), CD8+ (n=4), and CD4+ (n=1), and 2 of 3 ensuing EATLs. Genetic alterations were identified in 9/11 (82%) of the RCD II cases. All 9 displayed mutations in members of the JAK-STAT signaling pathway, including frequent, recurrent STAT3 (7/9, 78%) and JAK1 (4/9, 44%) mutations, and 9/10 evaluable cases expressed phospho-STAT3. The mutated cases also harbored recurrent alterations in epigenetic regulators (TET2, n=5 and KMT2D, n=5), nuclear factor-κB (TNFAIP3, n=4), DNA damage repair (POT1, n=3), and immune evasion (CD58, n=2) pathway genes. The CD4−/CD8− and other immunophenotypic subtypes of RCD II exhibited similar molecular features. Longitudinal genetic analyses of 4 RCD II cases revealed stable mutation profiles, however, additional mutations were detected in the EATLs, which occurred at extraintestinal sites and were clonally related to antecedent RCD II. Chromosome microarray analysis demonstrated copy number changes in 3/6 RCD II cases, and 1 transformed EATL with sufficient neoplastic burden for informative analysis. Our findings provide novel information about the immunophenotypic and genomic characteristics of RCD II, elucidate early genetic events in EATL pathogenesis, and reveal potential therapeutic targets.